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Biomedical subjects

D Hoppensteadt

Publications and source records attributed to D Hoppensteadt.

96 records · Page 6Linked to original sources
PubMed1984

Antithrombotic actions and pharmacokinetics of heparin fractions and fragments.

During the last few years many reports on the antithrombotic actions of low molecular weight fractions (LMF) have become available and are being tested in the experimental and clinical settings. Although derived from commercial heparins, the mode of antithrombotic actions, pharmacokinetics and physiologic disposition of these agents is distinct from the parent materials. The antithrombotic potency of these fractions is generally assigned in terms of their ability to inhibit serine proteases such as factor Xa and thrombin in the presence of antithrombin III (AT III). However, these agents are also reported to exert their antithrombotic actions via non AT III mediated inhibition of serine proteases (XIIa, IXa), activation of fibrinolysis via the release of plasminogen activators and charge transition on vascular surfaces. In order to evaluate the relative pharmacologic actions of heparin and its derivatives, we utilized defined animal models to obtain data in terms of pharmacologic parameters. Significant differences between heparin and its derivatives were evident. Human studies on the pharmacokinetics and the endogenous actions of these agents confirmed our preclinical findings. These studies suggest that well-defined preclinical studies are an essential element in the development of newer antithrombotic agents.

Animals↗
PubMed1983

Newer synthetic peptide substrates in coagulation testing: some practical considerations for automated methods.

More than 100 chromogenic and fluorogenic peptide substrates are now available for the evaluation of coagulation and related parameters. Many of these substrates exhibit undesirable physical properties, such as insolubility, surface adsorption, and interaction with endogenous plasma proteins. Some of these substrates are capable of inhibiting serine protease generation during activation in the global assay. In order to develop synthetic chromogenic substrates with desirable physical and biochemical characteristics, modified amino acids, such as CHG, CHT, and Nleu, have been utilized. Similarly, to provide a favorable molecular environment to facilitate enzyme and synthetic substrate interactions, various molecular manipulations, such as the introduction of bulky groups, is helpful in developing substrates for protein Ca and C1-esterase. Substrates for Factor Xa, CH3-O-CO-CHG-Arg-pNA (bovine Xa, Km 2.5 X 10(-4) M; human, Km 3.5 X 10(-4) M); thrombin, H-D-CHT-Ala-Arg-pNA (bovine thrombin, Km 3 X 10(-6) M; human thrombin, Km 6 X 10(-6) M); plasmin, H-D-Nleu-CHT-Lys-pNA (human plasmin, Km 2.2 X 10(-5) M) were found to have identical or superior biochemical characteristics to the earlier substrates. These newer substrates were found to be more soluble (greater than 5 X 10(-4) M) in physiologic buffer, less susceptible to autoamidolysis at reaction conditions, and did not produce opacity of the test solution in final concentrations of 5 X 10(-4) M. Comparable results on normal and pathologic plasma samples were obtained in various laboratory assays that utilize currently available substrates for Factors Xa and IIa, kallikrein, and plasmin (R = greater than 0.9). We propose that prior to the application of a new synthetic substrate in a given assay, a careful biochemical and physical screening of the substrate, the assay conditions, and the interaction of substrates with plasma proteins is highly desirable.

Blood Coagulation Factors↗
PubMedDate not supplied

Postburn edema and related changes in interleukin-2, leukocytes, platelet activation, endothelin-1, and C1 esterase inhibitor.

Interleukin-2 (IL-2) promotes multisystem organ edema, lung neutrophil sequestration, and platelet activation through alterations in the microvascular barriers and permeability. IL-2, complement, platelet, and vascular endothelial activation were evaluated in 60 patients. One-factor analysis of variance indicated a significantly increased absolute neutrophil count on day 1 (p < 0.0001) and decreased C1Inh, p = 0.0001, with elevated IL-2 levels in the 20% to 40% group (p = 0.008). Endothelin-1 levels were significantly increased in the 20% to 40% total body surface area group on day 5. The absolute neutrophil count was significantly reduced in both groups, and C1Inh rose to near normal levels by day 5. No significant elevations of 6-keto prostaglandin F1 alpha were observed on day 1 or day 5 in the < 40% total body surface area group; however, these levels were significantly elevated on day 1 in the > 40% total body surface area group. Thromboxane B2 and platelet factor 4 were significantly elevated in all groups (p = 0.001) on days 1 and 5. Regression analysis implicated infection as a significant contributor to the IL-2 variations (r2 = 0.61), with inhalation injury minimally affecting IL-2 plasma levels (r2 = 0.09). Generalized edema increased with increasing burn wound size in parallel with elevated IL-2 and endothelin-1 levels, reduced C1Inh levels, and leukocytosis in the first week after thermal injury. These data suggest that there are dynamic interactions among the endothelium, cytokine stimulation, leukocytosis, complement, and platelet activation in promoting the microvascular permeability.

Adolescent↗
PubMedDate not supplied

Low molecular weight heparins. An objective overview.

The introduction of low molecular weight heparins has added a new dimension to the management of thrombotic disorders. Ten LMWHs are currently available for clinical use. Although these agents have been primarily developed and used in European countries, other countries, including the US, have started to evaluate their usefulness. Well designed clinical trials have been carried out for different clinical indications with several of these products. In contrast to other prophylactic antithrombotic drugs (heparin, warfarin, aspirin), LMWHs have provided consistently impressive clinical results. Moreover, the other products have less desirable tolerability profiles than that of LMWHs. As shown in both experimental and clinical settings, the prophylactic antithrombotic efficacy of each LMWH is distinct in itself being characteristic to only that particular drug. Besides the currently available LMWH preparations, some 14 other agents are under development at this time. Although both the original and newer products have similar basic characteristics, the physicochemical properties and the pharmacological actions of each of these agents may differ significantly. All manufacturers should follow the Food and Drug Administration (FDA) guidelines and conduct their own clinical trials on each of their products. Many significant developments of LMWHs will take place in the coming years; in addition to development for prophylactic use, LMWHs will be developed for therapeutic intervention.

Heparin, Low-Molecular-Weight↗